1. Field of the Invention
The present invention relates generally to the field of antibodies. More particularly, the present invention describes identification and use of monoclonal antibodies and antibody fragments selectively directed to activated protein C (APC).
2. Description of Related Art
Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually give rise to a fibrin clot. Generally, blood components participating in the coagulation “cascade” are proenzymes or zymogens-enzymatically inactive proteins that are converted into an active form by action of an activator. Regulation of blood coagulation is largely accomplished enzymatically by proteolytic inactivation of the pro-coagulation factors Va and VIIIa achieved by activated protein C (APC) (Esmon, 1989).
Protein C is the precursor to APC, a potent natural anticoagulant. Protein C is activated by thrombin in complex with thrombomodulin (TM). The activation is augmented by endothelial cell protein C receptor (EPCR). TM and EPCR can be down-regulated due to inflammatory mediators, such as tumor necrosis factor, reviewed by Esmon (1999). TM and EPCR have also been found to be reduced in some forms of septic shock, meningococcemia in particular. Since EPCR and TM are expressed on endothelium, it is not possible to directly determine how well they are functioning without removal of blood vessels.
APC functions as an anticoagulant by proteolytically cleaving and downregulating pro-coagulant factors. APC also serves important functions as an anti-apoptosis agent, an anti-inflammatory molecule and a cytoprotectant. Bleeding disorders where homeostatis is dysregulated through a loss of a key factor, such as the absence of Factor VIII in heomphilia, or in trauma patients where the wound process results in a temporary loss of hemostasis, may be treated by the removal of APC. Such treatment, however, could result in unwanted detrimental consequences of removing the beneficial functions of APC in addition to the removal of the anti-coagulant activity. Therefore it is desirable to have a therapeutic that selectively targets the anti-coagulant activity of APC while leaving other functions of the molecule intact.